Ovarian cancer, like many other types of cancers, presents a paradox: the coexistence of tumor cells and tumor-specific T cells, indicating that a disconnect exists between the afferent and efferent arms of the immune system. However, the tumor-specific immune response in ovarian cancer is not wholly ineffective, as the presence of intratumoral T cells correlated with increased progression-free or overall survival. We hypothesize that tumor immunotherapy will complement existing ovarian cancer therapies and provide long-term disease-free survival. The current gold standard in tumor immunotherapy is dendritic cell (DC)-based tumor vaccines. However, the DC-based vaccine field is faced with major unresolved issues, including the high cost of DC preparation, batch-to-batch variability, and poor yields from in vitro culture. For these reasons, we have focused on development of genetically modified tumor cell-based vaccines. The advantages of this approach include MHC Class l-restricted presentation of the complete tumor antigen repertoire, and in the case of established tumor cell lines, an unlimited supply of vaccine material. As a foundation for this work, we have generated 14 cell lines from primary ovarian tumors, as well as banking lymphocytes from the peripheral blood and tumor environment. Thus, we have the resources to study tumor cell-based vaccines in a completely autologous setting. The central hypothesis underlying our work is that tumor cells can be converted into professional antigen-presenting cells, capable of directly activating and arming tumor-specific T cells. We will test the hypotheses underlying our strategy through performing the following Specific Aims: 1) Identify candidate ovarian cancer cell lines that will serve as the foundation for our vaccine, and modifying them to function as Antigen Presenting Tumor Cells (APTCs) by transducing them with lentiviral vectors encoding CD83, CD86, 4-1BBL, IL-7, IL-15, and CCL21. 2) Examine the ability of APTCs to induce tumor-specific cytotoxic CD8+ cell responses in vitro. 3) Test APTC function in vivo in a beta2-microglobulin(null)/NOD//scid mouse model, in both adoptive transfer and active immunization settings. Successful completion of these studies will yield information pertinent to the mechanisms underlying tumor vaccines, leading to improved subsequent vaccine generations. Furthermore, these studies will provide the foundation for conducting a clinical trial.
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